Project Summary Inflammatory bowel disease (IBD) is characterized by the development of an abnormal inflammatory response in the gastrointestinal tract. The microbiota of the intestinal tract, in part via interactions with the host epithelium and immune system are thought to drive this proinflammatory state. The gut microbiota represents a complex community of bacteria that until recently has only been partly characterized. The use of culture-independent techniques to examine complex microbial communities has started to reveal details about the structure and composition of the gut microbiota. To date, minimal work has been done to define differences in the structure of the mucosa-associated microbiota of the intestinal tract secondary to alterations in the host immune system, the presence of pathogens, antibiotic treatment or the presence of beneficial (probiotic) organisms. In this proposal, an existing collaboration between scientists with interests in microbial ecology and infectious diseases/bacterial pathogenesis plan to investigate the role of the intestinal microbiota in IBD utilizing a well developed murine model of IBD in IL-10-/- mice triggered by the presence of the bacterium Helicobacter hepaticus. Specifically we propose to 1) determine the influence of the host immune system on shaping the community structure of the mucosa-associated intestinal microbiota 2) determine how H. hepaticus infection and the development of colitis changes the mucosa-associated intestinal microbiota 3) determine if antibiotics can modify the development of IBD in H. hepaticus-infected IL-10-/- animals and 4) determine if probiotic bacteria prevent and/or ameliorate colitis by inducing shifts in the intestinal microbiota. The proposed experiments will provide insight into the mechanism by which infectious agents can trigger shifts in the indigenous microbiota that lead to aberrant host responses and disease states. This information will directly impact patients with inflammatory bowel disease, leading to a greater understanding of the underlying disease mechanisms and the development of novel treatment modalities. Relevance Inflammatory bowel disease in humans is thought to arise from an abnormal interaction between the immune system and the microbes that normally inhabit the gut. This project intends to define abnormalities in the community of gut microbes that predispose to the development of inflammatory bowel disease, pointing the way towards new therapies for this chronic disease that affects 1 in 1000 people in developed countries. [unreadable] [unreadable] [unreadable]